cAMP-mediated signaling pathways regulate a multitude of important biological processes under both physiological and pathological conditions, including diabetes, heart failure, and cancer. In eukaryotic cells, the effects of cAMP are mediated by two ubiquitously expressed intracellular cAMP receptors, the classic protein kinase A/cAMP-dependent protein kinase (PKA/cAPK) and the recently discovered exchange protein directly activated by cAMP/cAMP-regulated guanine nucleotide exchange factors (Epac/cAMP-GEF). Like PKA, Epac contains an evolutionally conserved cAMP-binding domain that acts as a molecular switch for sensing intracellular second messenger cAMP levels to control diverse biological functions. The existence of two families of cAMP effectors provides a mechanism for a more precise and integrated control of the cAMP signaling pathways in a spatial and temporal manner. Depending upon their relative abundance, distribution and localization, as well as the specific cellular environments, Epac and PKA may act independently, converge synergistically, or oppose each other in regulating a specific cellular function.

A pre-metastatic niche is a microenvironment prepared for the colonization of circulating tumor cells in specific organs. Exosomes are extracellular vesicles with a variety of biological functions. Exosomes play an irreplaceable role in the development of pre-metastatic niches, and mainly function as communication medium. In this review, we analyzed the effects of exosomes on pre-metastatic niches from various perspectives, including inflammation, immune response, angiogenesis, organotropism, matrix remodeling and biomarker expression. In particular, exosomes express programmed death ligand 1 (PD-L1) and cause the immune escape of tumor cells. The immunomodulatory effects of exosomes and their potential in liquid diagnosis have drawn our attention. The potential value of exosomes and pre-metastatic niches will be realized in the field of immunity therapy.

Hedgehog (Hh) signaling is deregulated in multiple human cancers including pancreatic ductal adenocarcinoma (PDA). Because KRAS mutation represents one of the earliest genetic alterations and occurs almost universally in PDA, we hypothesized that oncogenic KRAS promotes pancreatic tumorigenesis in part through activation of the Hh pathway. Here, we report that oncogenic KRAS activates hedgehog signaling in PDA cells, utilizing a downstream effector pathway mediated by RAF/ MEK/MAPK but not phosphatidylinositol 3-kinase (PI3K)/ AKT. Oncogenic KRAS transformation of human pancreatic ductal epithelial cells increases GLI transcriptional activity, an effect that is inhibited by the MEK-specific inhibitors U0126 and PD98059, but not by the PI3K-specific inhibitor wortmannin. Inactivation of KRAS activity by a small interfering RNA specific for oncogenic KRAS inhibits GLI activity and GLI1 expression in PDA cell lines with activating KRAS mutation; the MEK inhibitors U0126 and PD98059 elicit a similar response. In addition, expression of the constitutively active form of BRAF E600 , but not myr-AKT, blocks the inhibitory effects of KRAS knockdown on Hh signaling. Finally, suppressing GLI activity leads to a selective attenuation of the oncogenic transformation activity of mutant KRAS-expressing PDA cells. These results demonstrate that oncogenic KRAS, through RAF/MEK/ MAPK signaling, is directly involved in the activation of the hedgehog pathway in PDA cells and that collaboration between these two signaling pathways may play an important role in PDA progression. Pancreatic ductal adenocarcinoma (PDA)2 is the fourth leading cause of cancer-related death for both men and women in the United States. It was estimated that in 2006 33,730 new cases would be diagnosed, and 32,300 would die from the disease (American Cancer Society Cancer Facts and Figures 2006). Therefore, PDA is one of the most lethal human diseases, with a 5-year survival rate of less than 4% and a median survival of less than 6 months.PDA is one of the better-characterized neoplasms at the genetic level. There are now sufficient clinical, genetic, and pathological data to support a tumor progression model for PDA in which the pancreatic ductal epithelium progresses from normal to increased grades of pancreatic intraepithelial neoplasia to invasive cancer (1, 2). Accompanying the progressive morphological changes is the sequential accumulation of genetic alterations in the KRAS oncogene and the tumor suppressors INK4A, p53, and SMAD4/DPC4, although these alterations have not been linked to the acquisition of specific histopathological attributes (3-5). In addition to these frequent genetic abnormalities, mutations in the tumor suppressors BRCA2, TGFBR1, and TGFBR2, the serine-threonine kinases AKT2 and LKB1/STK11, and certain DNA mismatch-repair genes represent other less common genetic events in PDA (6 -11).Aberrant RAS activation plays a critical role in tumorigenesis; activating RAS mutations are found in 30% of all human cancers (12). Of all human can...

BRAF(V600E) is the most common oncogenic lesion in melanoma and results in constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and uncontrolled cell growth. Selective BRAF inhibitors such as vemurafenib have been shown to neutralize oncogenic signaling, restrain cellular growth and improve patient outcome. Although several mechanisms of vemurafenib resistance have been described, directed solutions to overcome these resistance lesions are still lacking. Herein, we found that vemurafenib resistance can be (i) mediated by EphA2- a member of the largest receptor tyrosine kinases (RTK) subfamily erythropoietin-producing hepatocellular (Eph) receptors and (ii) associated with a greater phenotypic dependence on EphA2. Furthermore, we developed a series of first-in-class EphA2 inhibitors and show that these new compounds potently induce apoptosis, suppress viability and abrogate tumorigenic growth of melanoma cells, including those that are resistant to vemurafenib. These results provide proof-of-concept that RTK-guided growth, and therapeutic resistance, can be prospectively defined and selectively targeted.